Neurotrophic factors are traditionally viewed as secretory proteins that regulate long-term neuronal survival and differentiation. Research in my lab focuses on the role of neurotrophic factors in synapse development and plasticity, a new area that has attracted much attention in recent years. We have made two important discoveries: 1) BDNF acutely potentiates high frequency synaptic transmission, and promotes hippocampal LTP, a cellular model for learning and memory. 2) NT3 facilitates the long-term maturation at developing neuromuscular junction (NMJ). This year, we have extended these lines of research. Our previous studies have indicated that enhancement of high frequency transmission contributes directly to BDNF-induced facilitation of LTP in the hippocampus. Using BDNF knockout mice, we now demonstrated that BDNF enhances high-frequency transmission by promoting synaptic vesicle docking in the CA1 synapses. We showed that this is achieved by up-regulating the docking protein synaptobrevin at the terminals through a mechanism independent of protein synthesis. Moreover, we demonstrated that BDNF- induced potentiation of high frequency transmission is mediated by signaling pathways involving MAP kinase and PI3 kinase, but not PLC-g. All these suggest that BDNF acts presynaptically to potential transmitter release, but we have not excluded the potential postsynaptic effects of BDNF on CA1 synapses. We are currently addressing this issue using a conditional knockout mouse line in which the BDNF receptors have been selectively deleted in postsynaptic CA1 neurons. In a separate line of work, we have compared the signaling mechanisms for BDNF and GDNF, using cultured neurons from substania nigra. We found that although both factors activate MAP kinase and the transcription factor CREB, there are substantial differences in their kinetics and pharmacology. We have further showed that differential signaling mechanisms by the two factors may lead to their different biological functions. While both potentiate transmitter release, BDNF but not GDNF, enhances the expression of synaptic protein while GDNF, but not BDNF, increases axonal fasciculation. Our future work will identify the functional role of GDNF at CNS synapses and the neuromuscular junction. - neurotrophins, transmission, synaptic plasticity, hippocampus, NMJ, LTP, knockout mice, culture, electrophysiology